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Report on a paraganglioma of the left division place of the carotid and the common occurrence with adenomas in other endocrine organs (hypophysis, thyroid gland, adrenal gland and pancrease) in the sense of an MEA-syndrome (multiple endocrine adenopathy) in a 75-year-old woman. Discussion of the morphologic findings as well as reference to the multiple occurrence of adenopathies from the APUD cell system.
The Authors after having paid considerable attention on the contemporary existence of numerous carcinoid tumours of the intestine and of other abdominal organs, as well as on the frequent multicentricity exhibited by the very same at the level of the last tract of the ileum, explain this by considering the recent research performed on the APUD cells and on the cells of the diffuse endocrine system (DES) of the intestine. They present a carcinoid case, where it is understood that the product of secretion of the same, still not completely identified in its structure and mode of action, produces an arterial vascular alteration even at considerable distance from the tumour, hence bringing about an intestinal ischemic symptomatology which they hypothesize is the case for all the cells of the intestinal diffuse endocrine system, a type of self-regulatory feed-back hormonal system.
Neuroendocrine pancreatic tumors are neoplasms derived from APUD cells, characterized by hyperincretion of several peptides of hormonal activity. The incidence of these tumor is low. They are usually classified according to the predominant secreted peptide: gastrinoma, insulinoma, VIPoma, glucagonoma. Insulinoma is the most frequent endocrine pancreatic tumor, characterized by a peculiar clinical picture due to insulin action. This neoplasm is prevalently benign (90%), and may cause symptoms due to hypo-glycemia such as epilepsy, asthenia, deep coma, dizziness, hunger and epigastric pain. Surgery still constitutes the principal therapy for insulinoma treatment, but an accurate tumor identification is necessary. Selective arteriography of the pancreas and new diagnostic investigations as intraoperative US, selective sampling of pancreatic veins with insulin Quick-RIA, aid the diagnosis and more precise localization of the tumor. When surgical therapy is not practicable, for diffuse metastases, octreotide has an inhibitory effect upon hormone release, and may be combined with chemotherapy for controlling clinical symptoms. We review the clinical records of 2 patients from our Institute, who had hyper-insulinism due to benign insulinomas of the tail of the pancreas. Surgical treatment was performed with enucleation of the neoplasms.
A 1-year-old boy had intractable diarrhea and symptoms of the watery-diarrhea-hypokalemia-achlorhydria (WDHA) syndrome, a well-known entity in adults. Resection of a ganglioneuroblastoma situated in the neck caused prompt relief of symptoms. The ganglioneuroblastoma in this instance contained the enterohormone vasoactive intestinal peptide (VIP); blood levels of this peptide were elevated preoperatively. After tumor resection, the VIP level returned to normal, and the diarrhea ceased on the day of the operation. The genesis of the diarrhea in relation to the production of polypeptides from neuroendocrine origin is discussed (APUD-cell concept). VIP may be the mediator of the WHDA syndrome in ganglioneuroblastoma.
A total of 100 patients were examined: 35 patients with biliary dyskinesia, 44 patients with chronic acalculous cholecystitis, 21 patients with chronic calculous cholecystitis. The patients were evaluated clinically with investigation of motor-evacuation function of the gall-bladder, activity of inflammation in the gall-bladder, bile lithogenicity, morphofunctional characteristics of the stomach APUD-cells and degree of Helicobacter pylori contamination. Chronic calculous cholecystitis is characterized by clearcut symptoms, hypomotor dyskinesia, high cholesterol, signs of diffuse atrophic gastritis. Chronic acalculous cholecystitis with hypomotor dyskinesia was accompanied by mild intoxication, presence of C-reactive protein, high cholesterol, diffuse atrophic gastritis.
Amine precursor uptake and decarboxylation (APUD) small-granule cells were stained by periodic acid-Schiff (PAS)-lead hematoxylin in 0.5-micron etched Epon sections of adult hamster lung fixed for transmission electron microscopy. The leading edge of a small-granule cell cluster was identified in a segmental bronchus as a single PAS-positive cell. From 256 serial thin sections through its entirety, a three-dimensional wooden reconstruction of the cluster and morphometric estimates of the apical and basal surfaces, cell volume, and intracytoplasmic distribution of mitochondria and small granules was made. Of moderate size, the body consisted of 16 small-granule cells, 11 forming its ovoid core with five outlying cells diverging at the margin; these were pyramidal, possessing wide bases and thin apical processes. At the bronchial surface, processes from the 11-cell core emerged together, whereas the divergent cells emerged in groups of two and three. Ten Clara-like cells and one ciliated cell encircled the core. Altogether they formed a pseudostratified epithelium in contrast to the surrounding simple columnar epithelium. Deeper in the cluster, numerous cytoplasmic extensions interdigitated with those from adjacent cells, and toward the base the Clara-like and APUD cells were increasingly interposed. In marked contrast to the apical cytoplasm, the infranuclear cytoplasm of the latter was densely packed with ca. 1,000 A electron-dense granules; and the basal, presumptively secretory face of each cell was five to six times greater than the area exposed to the bronchial lumen. Judged by granule size and ultrastructure, only one APUD cell type was recognized in the reconstructed cluster. Beneath it many fibrocytic processes were separated from the APUD cells by only the thickness of the basal lamina. Two fascicles of smooth muscle approached the cluster within 0.4-0.8 micron. Unmyelinated nerve fibers came as close but contacted only the muscle. Capillaries, in contrast, came no closer than 15 micron from the base of the body. Evidently, 1) fibrocytes and smooth muscle are more likely targets for secretions from such a paracrine body than cells reached through the blood-stream, and 2) not all small-granule cell clusters are innervated.
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The small oat cell type of carcinoma is only rarely seen in extrapulmonary sites. To date, nineteen cases have been described in the oesophagus, almost all by Japanese authors. In this report we review the relevant literature and add one more case of pure type to the total. The histopathological, histochemical and ultrastructural findings and the similarity of this tumour to the oat cell bronchial carcinoma, lead one to propose that it originates in the cells of the APUD series, which have been demonstrated in the normal oesophageal epithelium. Thus is represents on endocrine carcinoma of the oesophagus.
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The neuron-specific enolase (NSE) level is elevated in neurons and in numerous cells of the APUD system; melanocytes are also considered to belong to this system. In order to test the relevance of NSE as a tumour marker for malignant melanoma, its concentration in serum was radioimmunologically determined in 89 patients with melanomas: 24 in stage I (primary tumours), 44 in stage II (regional metastases), and 21 in stage III (distant metastases). The average (+/- coefficient of variation) concentrations recorded were 7.4 micrograms/l (+/- 46%) in patients in stage I, 5.8 micrograms/l (+/- 32%) in those in stage II, and 11.0 micrograms/l (+/- 72%) in those in stage III. A threshold value of 11.5 micrograms/l was exceeded in 9 cases, including 8 patients in stage III. Since definitely increased values arose almost exclusively in distant metastases, determination of NSE levels in serum is hardly a suitable tool for early detection of latent metastases.
The submaxillary glands of young rats were examined in vivo and in vitro. Yellow fluorescence in some cells treated with o-phthalaldehyde was observed and they yielded a positive reaction on staining with phosphotungstic acid haematoxylin indicating the presence of glucagon. These cells were localized between secretory endpieces of the gland. In rats treated with L-5-hydroxytryptophan (L-5-HTP) cells similar in shape and size showed yellow fluorescence after the action of formaldehyde vapour. The results of histochemical studies and ultrastructural analysis seem to indicate the presence of cells similar to APUD endocrine cells in the rat submaxillary gland.
Lungs of 4 human fetuses (11-, 13-, 22-, 28-week-old), of 1 stillborn and of 3 mature persons, operated in connection with pulmonary cancer, have been investigated. In the fetal lungs apudocytes and neuroepithelial bodies (NEB) have been revealed. The apudocytes differ from each other by structure and size of endocrine granules. In the 11-week-old fetus P1 cells with two types of granules occur most often. Among P1 cells there are several subgroups, differing in their granule dimensions. P2 apudocytes possess granules of one type with a round core and a narrow rim of cytoplasm. P3 cells are characterized with still larger granules, a very dense core and a narrow rim. In large bronchi some groups are found, consisting of two and more endocrine cells of all three types. In the lungs of the 13-week-old fetus P1 cells are defined and a new type of cells, that contain homogenous granules, characterizing by their small size. In 22 weeks of development in the intrapulmonary bronchi apudocytes with granules specific for Ec-cells are found. NEB consists of cells and islands, possessing polymorphous granules. Various types of apudocytes are defined in large bronchi of the 22-week-old fetus. In the stillborn infant apudocytes in the lung are found very seldom. In lung of the mature persons the morphology of apudocytes is unitypical. Thus, during embryogenesis and after birth there are variable types of endocrine cells and NEB.
Thirtyfive biologically active peptides are products of the 40 cells of the APUD series, which constitute the Diffuse Neuroendocrine System (DNES). Twentyone of these peptides are found not only in the cells and processes of the DNES but also in the cells and the processes of the nervous system. Hence the appellation common. To the seven original common cytochemical features of the APUD cells it is possible to add the positive results of 3 subsidiary staining techniques (Lead haematoxylin, Argyrophilia, Formaldehyde-Fluorescamine), a singly cytochemical method (Formaldehyde-ozone), and an immunocytochemical molecular marker method (neuron-specific enolase; NSE). Application of this last method demonstrates NSE in the APUD cells and confirms their origin from "neuroendocrine-programmed epiblast."
A 28 year old white women was found to have a cervical tumor in the 25th week of pregnancy. Pathologic examination revealed a nonkeratinizing small cell carcinoma. After delivery by cesarean section, pelvic lymph node exploration was carried out, and all 15 nodes were free of tumor. Her condition was staged as II-A, and she was treated with local radiation. Metastatic disease became manifest almost a year later and was histologically similar to her primary disease. A Cushingoid appearance was noticed and plasma cortisol levels were elevated. Twenty-four hour urinary 17-hydroxycorticosteroid (17-OHCS) and 17-ketosteroid (17-KS) levels were elevated and failed to suppress with dexamethasone. Plasma adrenocorticotropin (ACTH) level was elevated. Electron microscopic examination of the tumor tissue revealed neurosecretory granules. Immunoperoxidase stains for ACTH were positive. The patient's course was one of progressive decline and eventual death. A literature review revealed two other cases in which carcinoma of the uterine cervix was considered to be the source of ectopic ACTH. Some small cell carcinomas of the cervix may arise from cells of the APUD series. Small cell carcinoma of the uterine cervix may behave differently from the more commonly encountered keratinizing and large cell nonkeratinizing carcinomas of the cervix and may not respond as well to standard therapy. Ectopic hormone production, production of abnormal peptides or of vasoactive amines may be more common in small cell carcinoma of the cervix than is currently recognized, and these products may be clinically useful as tumor markers.
In the Vertebrata the great majority of cells producing hormonal peptides belong to the APUD series and share its distinctive cytochemical and ultrastructural characteristics. According to the concept all members of the series are to be regarded as derivatives of neuroectoderm or of specialized (placodal) ectoderm. For most of the APUD cells this criterion is fulfilled in that their origin from neural tube, neural ridges or neural crest can be considered proven. Complete proof is not yet available for the APUD cells of the gastrointestinal tract and pancreas, and indeed much contrary evidence can be cited. Despite the latter, our embryological studies show: (1) that the hypothalamohypophyseal complex is wholly neuroectodermal; (2)that the chronology of neural crest dispersion is such that this tissue could be responsible for observed APUD cell contributions to the foregut; (3) that placodal ectoderm makes important contributions to pharyngeal pouch endocrine derivatives in birds and mammals; and (4) that the amphibian parathyroid gland is derived from the same layer of neural ectoderm as the hypothalamo-hypophyseal axis. Supporting immunocytochemical studies indicate that peptides belonging to the APUD series are more widely distributed than hitherto recognized and it is concluded: (1) that the whole of peptide endocrinology is neuroendocrinology; and (2) that the APUD cells, with a few cells hitherto regarded as being outside the series, form a third (Endocrine) division of the nervous system to add to the existing Somatic and Autonomic divisions.
Small-granule APUD (amine precursor uptake and decarboxylation) endocrine cells were surveyed in 600 3 microns glycol methacrylate-embedded, periodic acid-Schiff (PAS)-lead hematoxylin-stained serial sections comprising 95% of the infracardiac lobe of a hamster lung. Results were confirmed by less systematic study of other hamster lungs. Positions of endocrine cells were marked on cardboard profiles of bronchi and bronchioles for assembly into a 70 X enlarged three-dimensional model from which size and branching of the airway were determined. Records were made for computer analysis of the number and staining patterns of endocrine cells, the nature of contiguous epithelial cells, and the presence of underlying smooth muscle and blood and lymph vessels. APUD cells occurred in 95% of all airways, at a mean density of six solitary cells and 10 cell clusters (neuroepithelial bodies) per millimeter of airway length, measured along the bronchial-bronchiolar long axis. Nineteen percent of endocrine cell loci (29% of all cells) were found at bronchioloalveolar portals in all regions of peripheral lung. Twenty percent of loci (28% of all cells) occurred about the origins of lateral airway branches; these included 4% of loci on carinal points of bifurcation. Two groups of APUD cells had distinctive anatomic relationships: 1) 13% of loci (20% of cells) were related to pulmonary capillaries and venules, mainly at bronchioloalveolar portals; and 2) 39% of loci (53% of cells) overlaid peribronchial muscle, mainly in larger airways where changes in diameter might affect ventilation. In this lobe, APUD cells were not related to goblet or mast cells; 74% of loci abutted Clara and/or ciliated cells, 17% great alveolar cells. Few loci were associated with pulmonary arteries and veins. Five APUD cell types were identified by PAS-lead hematoxylin staining. Types I, II, and V, with granules approximately 0.2 micron in diameter, made up 38%, 45%, and 2% of cells, respectively. Types III and IV, 10% and 5% of cells, respectively, had larger granules. Types I, II, III, and V occurred as solitary cells as well as in neuroepithelial bodies. One-third of the neuroepithelial bodies contained a single cell type; the rest were mixed. Type IV cells, with coarse lead hematoxylin-positive granules, usually were found in large neuroepithelial bodies containing two to four cell types and were never seen occurring alone. We conclude that 1) hamster lungs contain different kinds of APUD cells; 2) those likely have a variety of functions; 3) distinctions merely between solitary and clustered cells may not be significant; 4) the histophysiology of many neuroepithelial bodies probably is more complex than previously suspected; and 5) PAS-lead hematoxylin is superior to argyrophilia and amine fluorescence for light microscopic counting and analysis of pulmonary APUD cells in this species.
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The epithelium of the intrapulmonary airways of the chicken lung has been studied by fluorescence and electron microscopy. Numerous intensely yellow-fluorescent cells occur in the epithelium of the primary and secondary bronchi. The cell cytoplasm contains characteristic granular vesicles with an electron-dense central core. The vesicles react positively to chromaffin and argentaffin treatment, indicating that they are possible storage sites for amines. Synapse-like junctions occur between the granular cells and the intraepithelial nerve endings, filled with numerous mitochondria, suggesting that these granular cells may have a dual function as both receptor and endocrine cell.